The advantage of drugs that are capable of selectively targeting a specific cell type is well recognized. Thus, designing such selective drugs is a field of intense study. Such drugs are often, but by no means always, anticancer drugs.
Of importance in this regard, are drugs (or pro-drugs) that are bound to a marker. The purpose of the marker is to direct the drug to a marker-specific target cell. For example, binding drugs to antibodies for the purpose of targeting antibody-specific cells, such as tumor cells, is well known.
Binding a marker directly to a drug is, however, not always feasible. In addition, binding a marker directly to a drug often has the effect of dramatically reducing the efficacy of the drug, or disabling the action of the drug completely.
One approach to reducing the loss of efficacy of a drug bound to a marker is to bind the marker to the drug in a way that causes the drug to be released at the target in its most active form (usually the parent drug itself. In this regard, there has been intense interest in finding heterobifunctional compounds, or linkers, that not only bind a marker and a drug, but that also cause the drug to be released in its most active form at the appropriate time.
For example, U.S. Pat. No. 4,880,935 to Thorpe and U.S. Pat. No. 5,936,092 to Shen, et al. disclose heterobifunctional compounds that contain a disulfide group at one end and a carboxylate group at the other end. A cytotoxin is bound to the disulfide group at one end. An antibody is bound to the carboxylate group at the other end. Once in the targeted cell, the disulfide bond is cleaved by endogenous disulfide-reducing peptides, such as glutathione (GT). Cleavage of the disulfide bond releases the parent cytotoxin inside the targeted cell.
Similarly, U.S. Pat. No. 5,137,877 to Kaneko, et al., disclose heterobifunctional compounds that contain a hydrazinyl group at one end and a disulfide group at the other end. An anthracycline-based cytotoxin is bound to the hydrazinyl group. An antibody is bound to the disulfide group. The more acidic environment of the target cells causes hydrolysis of the hydrazinyl group. Hydrolysis of the hydrazinyl group releases the parent cytotoxin.
However, a demonstrated release of the drug at a target does not necessarily make the heterobifunctional compound medically effective or desirable. Medical efficacy depends to a significant extent on the rate of release of the drug by the heterobifunctional compound.
Accordingly, there have been efforts to increase the rates of release of drugs at a specified target by designing new heterobifunctional compounds. Most notable are efforts to design heterobifunctional compounds that, when hydrolyzed, undergo a favorable cyclization reaction to release the drug.
For example, Y. Ueda et al., Bioorganic & Medicinal Chemistry Letters, 1993, Vol. 3, No. 8, 1761-1766, disclose linkers that undergo phosphatase-initiated lactonization of phosphonoxyphenylpropionate derivatives of Taxol. The lactonization results in the in vivo release of the parent Taxol. As shown in Ueda et al., the purpose of Ueda's phosphonoxyphenylpropionate group is to increase the water solubility of Taxol.
R. B. Greenwald et al., J. Med. Chem., 2000, 43, 475-487, disclose ester-containing compounds linked to a drug to form a pro-drug. The pro-drug is hydrolyzed by an esterase, which results in a lactonization reaction. The lactonization reaction releases the drug.
K. Achilles, Arch. Pharm. Pharm. Med. Chem., 2001, 334, 209-215, discloses esterase-initiated lactonization of heterobifunctional compounds containing a peptide binding agent and a pro-drug. The lactonization causes release of the drug. The peptides bind to polymorphonuclear elastase, a serine protease associated with numerous medical conditions, including cancer.
Similarly, B. Wang et al. J. Org. Chem., 1997, 62, 1363-1367, disclose esterase-initiated lactonization of prodrugs containing cyclic peptides as binding agents.
However, the efficacy of conjugates of the heterobifunctional compounds described above is, in the vast majority of cases, far from clinically useful. For example, it would be particularly beneficial to increase the rates of drug release of such conjugates in order to be clinically effective.
Such targeted and effective rates of release of drugs have not yet been realized. In the case of targeting tumor cells, such high rates of release of anti-cancer drugs are particularly critical in light of the known high proliferation of cancer cells in tumors.
In addition, the drug conjugate containing a linker should release the most active form of the drug. See I. Ojima, X. Geng, X. Wu, C. Qu, C. P. Borella, H. Xie, S. D. Wilhelm, B. A. Leece, L. M. Bartle, V. S. Goldmacher, and R. V. J. Chari, J. Med. Chem. 45, 5620-5623 (2002).
Taxol, a diterpene natural product, has gained prominence as one of the most efficacious anticancer drugs. See E. K. Rowinsky, Annual Review of Medicine 1997, 48, 353; M. Suffness, Taxol Science and Applications; CRC Press: New York, 1995. Even more promising congeners of Taxol, termed taxoids (Taxol-like compounds), with orders of magnitude higher potency than Taxol have been developed. See G. I. Georg, T. Chen, I. Ojima, and D. M. Vyas (Eds.), “Taxane Anticancer Agents: Basic Science and Current Status”, ACS Symp. Series 583; American Chemical Society, Washington, D. C., 1995); I. Ojima, et al, Bioorg. Med. Chem. Lett., 1999, 9, 3423-3428; I. Ojima, et al, J. Med. Chem., 1996, 39, 3889-3896; and I. Ojima, G. D. Vite, K.-H. Altmann (Eds.), “Anticancer Agents: Frontiers in Cancer Chemotherapy”, ACS Symp. Series 796, American Chemical Society, Washington, D. C., 2001.
However, Taxol, taxoids, and other cytotoxic anticancer drugs contain drawbacks, including high toxicity to normal cells, poor water solubility, and emergence of drug-resistance. Therefore, there has been particular interest in selectively and efficiently targeting tumor cells with cytotoxic anticancer drugs. See, for example, K. Achilles, Arch. Pharm. Pharm. Med. Chem., 2001, 334, 209-215, and U.S. Pat. No. 5,137,877 to Kaneko, et al. R. V. J. Chari, Advanced Drug Delivery Reviews, 1998, 31, 89-104; M. L. Disis and M. A. Cheever, Advances in Cancer Research, 1997, 71, 343-371; H. Bier, T. Hoffmann, I. Haas, A. Van Lierop, Cancer Immunology Immunotherapy, 1998, 46, 167-173; G. A. Pietersz, B. Toohey, I. F. C. McKenzie, Journal of Drug Targeting, 1998, 5, 109-120; P. R. Hamann, L. M. Hinman, I. Hollander, C. F. Beyer, D. Lindh, R. Holcomb, W. Hallett, H.-R. Tsou, J. Upeslacis, D. Shochat, A. Mountain, D. A. Flowers, I. Bernstein, Bioconjugate Chemistry, 2002, 13, 47-58; Firestone, R. A.; Dubowchik, G. M. In Eur. Pat. Appl. EP 0624377 (Bristol-Myers Squibb Co. USA)1994; A. Safavy, K. P. Raisch, M. B. Khazaeli, D. J. Buchsbaum, J. A. Bonner, Journal of Medicinal Chemistry, 1999, 42, 4919-4924; C. Li, D. Yu, T. Inoue, D. J. Yang, L. Milas, N. R. Hunter, E. E. Kim, S. Wallace, Anti-Cancer Drugs, 1996, 7, 642-648; Pendri, A.; Conover, C. D.; Greenwald, R. B. Anti-Cancer Drug Design, 1998, 13, 387; C. Li, D.-F. Yu, R. A. Newman, F. Cabral, L. C. Stephens, N. Hunter, L. Milas, S. Wallace, Cancer Research, 1998, 58, 2404-2409; W. C. Rose, J. L. Clark, F. Y. F. Lee, A. M. Casazza, Cancer Chemotherapy and Pharmacology, 1997, 39, 486-492; J. J. Correa, M. Page, Tumor Targeting in Cancer Therapy, 2002, 165-178; V. Guillemard, H. U. Saragovi, Cancer Research, 2001, 61, 694-699; I. Ojima, X. Geng, X. Wu, C. Qu, C. P. Borella, H. Xie, S. D. Wilhelm, B. A. Leece, L. M. Bartle, V. S. Goldmacher, and R. V. J. Chari, J. Med. Chem. 45, 5620-5623 (2002).
Thus, there is a need for improving, inter alia, the specificity of drug delivery and the rates of release of various of drugs, including anticancer drugs. To achieve the above, there is a need for improved heterobifunctional linkers that bind a drug to a cell-specific marker, and that release the most active form of the drug in the target cell. There is a particular need for heterobifunctional linkers that selectively target tumor cells with highly potent cytotoxic drugs at a drug release rate that is effective for the destruction and/or inhibition of tumor cells.